12 research outputs found
Increased levels and defective glycosylation of MRPs in ovarian carcinoma cells resistant to oxaliplatin
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Modulation of sensitivity to platinum compounds in ovarian carcinoma cell systems
PAF1c links S-phase progression to immune evasion and MYC function in pancreatic carcinoma
Abstract In pancreatic ductal adenocarcinoma (PDAC), endogenous MYC is required for S-phase progression and escape from immune surveillance. Here we show that MYC in PDAC cells is needed for the recruitment of the PAF1c transcription elongation complex to RNA polymerase and that depletion of CTR9, a PAF1c subunit, enables long-term survival of PDAC-bearing mice. PAF1c is largely dispensable for normal proliferation and regulation of MYC target genes. Instead, PAF1c limits DNA damage associated with S-phase progression by being essential for the expression of long genes involved in replication and DNA repair. Surprisingly, the survival benefit conferred by CTR9 depletion is not due to DNA damage, but to T-cell activation and restoration of immune surveillance. This is because CTR9 depletion releases RNA polymerase and elongation factors from the body of long genes and promotes the transcription of short genes, including MHC class I genes. The data argue that functionally distinct gene sets compete for elongation factors and directly link MYC-driven S-phase progression to tumor immune evasion
A MYC-aurora kinase A protein complex represents an actionable drug target in p53-altered liver cancer
Egg pecking and puncturing behaviors in shiny and screaming cowbirds: effects of eggshell strength and degree of clutch completion
Abstract: Shiny cowbirds (Molothrus bonariensis) are generalist brood parasites that use hosts varying in body and egg size. On the contrary, screaming cowbirds (M. rufoaxillaris), which are larger than shiny cowbirds, are host specialist that use mainly one host of similar body and egg size. Both parasites peck and puncture eggs when visiting nests. Through puncturing eggs, cowbirds can reduce the competition for food their chicks face (reduction of competition hypothesis), but the same behavior could also be a mechanism to enforce host to renest when nests are found late in the nesting cycle (farming hypothesis). Eggshell strength increases the difficulty to puncture eggs and therefore may modulate egg-pecking behavior. To test these hypotheses, we studied the effect of the degree of clutch completion and egg size on egg-puncturing behavior. Moreover, we evaluated if morphological differences between cowbird species and eggshell strength affected egg-pecking behavior. We presented captive females a nest with complete (four eggs) or incomplete (one egg) clutches of house wren (small egg size, low eggshell strength), chalk-browed mockingbird (large egg size, intermediate eggshell strength), or shiny cowbird (medium egg size, high eggshell strength). The proportion of nests with punctured eggs was similar for complete and incomplete clutches. Cowbirds punctured more eggs in complete than in incomplete clutches, but in complete clutches, they did not destroy the entire clutch. There were no differences in the egg-pecking behavior between cowbird species, which pecked more frequently the eggs with the strongest eggshell. Our findings are consistent with the reduction of competition hypothesis. Significance statement: Brood parasitic birds do not build nests and raise their chicks. Instead, they lay eggs in nests of other species (hosts), which carry out all parental care. Some brood parasites, like the cowbirds, peck and puncture eggs when they visit host nests. This behavior may help to reduce the competition for food that their chicks face in the nest (reduction of competition hypothesis) or may enforce hosts to renest (farming hypothesis). We experimentally studied egg-pecking and egg-puncturing behaviors in the host generalist shiny cowbird and the host specialist screaming cowbird. We found that the degree of clutch completion and egg size modulate egg-puncturing behavior and eggshell strength modulates egg-pecking behavior. Our results indicate that by puncturing eggs, cowbirds reduce nest competition.Fil: Cossa, Natalia Andrea. Consejo Nacional de Investigaciones CientÃficas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de EcologÃa, Genética y Evolución de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de EcologÃa, Genética y Evolución de Buenos Aires; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de EcologÃa, Genética y Evolución; ArgentinaFil: Tuero, Diego Tomas. Consejo Nacional de Investigaciones CientÃficas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de EcologÃa, Genética y Evolución de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de EcologÃa, Genética y Evolución de Buenos Aires; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de EcologÃa, Genética y Evolución; ArgentinaFil: Reboreda, Juan Carlos. Consejo Nacional de Investigaciones CientÃficas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de EcologÃa, Genética y Evolución de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de EcologÃa, Genética y Evolución de Buenos Aires; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de EcologÃa, Genética y Evolución; ArgentinaFil: Fiorini, Vanina Dafne. Consejo Nacional de Investigaciones CientÃficas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de EcologÃa, Genética y Evolución de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de EcologÃa, Genética y Evolución de Buenos Aires; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de EcologÃa, Genética y Evolución; Argentin
The density and spatial tissue distribution of CD8+ and CD163+ immune cells predict response and outcome in melanoma patients receiving MAPK inhibitors
Background: Clinical response to MAPK inhibitors in metastatic melanoma patients is heterogeneous for reasons still needing to be elucidated. As the patient immune activity contributes to treatment clinical benefit, the pre-existing level of immunity at tumor site may provide biomarkers of disease outcome to therapy. Here we investigated whether assessing the density and spatial tissue distribution of key immune cells in the tumor microenvironment could identify patients predisposed to respond to MAPK inhibitors. Methods: Pretreatment tumor biopsies from a total of 213 patients (158 for the training set and 55 for the validation set) treated with BRAF or BRAF/MEK inhibitors within the Italian Melanoma Intergroup were stained with selected immune markers (CD8, CD163, β-catenin, PD-L1, PD-L2). Results, obtained by blinded immunohistochemical scoring and digital image analysis, were correlated with clinical response and outcome by multivariate logistic models on response to treatment and clinical outcome, adjusted for American Joint Committee on Cancer stage, performance status, lactate dehydrogenase and treatment received. Results: Patients with high intratumoral, but not peritumoral, CD8+ T cells and concomitantly low CD163+ myeloid cells displayed higher probability of response (OR 9.91, 95% CI 2.23-44.0, p = 0.003) and longer overall survival (HR 0.34, 95% CI 0.16-0.72, p = 0.005) compared to those with intratumoral low CD8+ T cells and high CD163+ myeloid cells. The latter phenotype was instead associated with a shorter progression free survival (p = 0.010). In contrast, PD-L1 and PD-L2 did not correlate with clinical outcome while tumor β-catenin overexpression showed association with lower probability of response (OR 0.48, 95% CI 0.21-1.06, p = 0.068). Conclusions: Analysis of the spatially constrained distribution of CD8+ and CD163+ cells, representative of the opposite circuits of antitumor vs protumor immunity, respectively, may assist in identifying melanoma patients with improved response and better outcome upon treatment with MAPK inhibitors. These data underline the role of endogenous immune microenvironment in predisposing metastatic melanoma patients to benefit from therapies targeting driver-oncogenic pathways
The density and spatial tissue distribution of CD8+ and CD163+ immune cells predict response and outcome in melanoma patients receiving MAPK inhibitors.
Background: Clinical response to MAPK inhibitors in metastatic melanoma patients is heterogeneous for reasons still needing to be elucidated. As the patient immune activity contributes to treatment clinical benefit, the pre-existing level of immunity at tumor site may provide biomarkers of disease outcome to therapy. Here we investigated whether assessing the density and spatial tissue distribution of key immune cells in the tumor microenvironment could identify patients predisposed to respond to MAPK inhibitors. Methods: Pretreatment tumor biopsies from a total of 213 patients (158 for the training set and 55 for the validation set) treated with BRAF or BRAF/MEK inhibitors within the Italian Melanoma Intergroup were stained with selected immune markers (CD8, CD163, β-catenin, PD-L1, PD-L2). Results, obtained by blinded immunohistochemical scoring and digital image analysis, were correlated with clinical response and outcome by multivariate logistic models on response to treatment and clinical outcome, adjusted for American Joint Committee on Cancer stage, performance status, lactate dehydrogenase and treatment received. Results: Patients with high intratumoral, but not peritumoral, CD8+ T cells and concomitantly low CD163+ myeloid cells displayed higher probability of response (OR 9.91, 95% CI 2.23-44.0, p = 0.003) and longer overall survival (HR 0.34, 95% CI 0.16-0.72, p = 0.005) compared to those with intratumoral low CD8+ T cells and high CD163+ myeloid cells. The latter phenotype was instead associated with a shorter progression free survival (p = 0.010). In contrast, PD-L1 and PD-L2 did not correlate with clinical outcome while tumor β-catenin overexpression showed association with lower probability of response (OR 0.48, 95% CI 0.21-1.06, p = 0.068). Conclusions: Analysis of the spatially constrained distribution of CD8+ and CD163+ cells, representative of the opposite circuits of antitumor vs protumor immunity, respectively, may assist in identifying melanoma patients with improved response and better outcome upon treatment with MAPK inhibitors. These data underline the role of endogenous immune microenvironment in predisposing metastatic melanoma patients to benefit from therapies targeting driver-oncogenic pathways